PET is a method that includes administering, into a living body, a compound labeled with a positron-emitting, short-lived radionuclide, measuring gamma rays generated by the labeled compound (hereinafter referred to as “tracer”) with a PET camera (a detector comprising a gamma ray scintillator and a photomultiplier), and imaging the body distribution of the labeled compound. PET is used in a nuclear medicine examination method to identify tumor sites such as cancer cells, diagnosis of Alzheimer disease, brain infarction, etc., diagnosis of mental disorders such as depression, treatment evaluation, pharmacokinetic evaluation, and drug efficacy evaluation.
PET is performed using a tracer labeled with a short-lived radionuclide such as 11C or 18F. In particular, 11C, labeled tracers have many advantages as described below.
(1) The application range of 11C-labeled tracers is very wide, because the carbon atom to be used exists in all organic compounds.
(2) Precursor compounds such as 11CH3I, 11CO, and 11CO2 for use in the synthesis of 11C-labeled tracers are prepared by well-established methods, and purified precursors are constantly available.
(3) Since 11C-containing tracers have a short half-life (20.3 minutes), many trial experiments for fundamental researches or many clinical tests can be performed in a day, and there is no need to pay special attention to the treatment of radiolabeled by-products generated after the synthesis reaction.
Therefore, 11C-labeled tracers can be considered to be the most ideal tracers for use in PET. However, since 11C has a very short half-life of 20 minutes, the process including the start of reaction, purification of the product, and administration has to be performed within 40 minutes. Therefore, the reaction for the synthesis of the tracers has to be completed within about 5 to 10 minutes. Methods for performing such rapid reaction in high yield have not been established yet, and this provides a problem when 11C-labeled tracers are used in PET.
Methods for synthesizing PET tracers using 11C as a radionuclide include methods of bonding a 11C-labeled methyl group to a hetero atom such as O, S, or N; and methods of bonding a 11C-labeled methyl group to a carbon atom of a carbon skeleton. Tracers having a 11C-labeled methyl group bonded to a hetero atom such as O, S, or N are often quickly converted into other compounds through metabolism. Therefore, such tracers have the disadvantage that when clinically used, such tracers are changed until they reach the target organ, so that proper diagnosis or treatment may be impossible. Such tracers are also not suitable as means for searching candidate compounds for drug development, because the methylated compounds may exhibit biological activity completely different from that of the compounds before the methylation.
In contrast, tracers having 11C methyl bonded to a carbon atom of a carbon skeleton have advantages as described below. (1) The methyl group is a sterically smallest, non-polar functional group and therefore has a minimum effect on the biological activity of parent compounds after it is introduced, which provides a high degree of freedom for molecular design and is suitable for candidate compound screening for drug development. (2) C-methylated products are more stable in metabolic processes than O- or N-methylated products and therefore allow production of highly reliable images and proper diagnosis or treatment of diseases.
Under the circumstances, the inventors have developed a method for rapidly methylating in which methyl iodide and an organotin compound are subjected to Stille coupling reaction, which has received attention (Non-Patent Document 1). This method enables cross-coupling between sp2-sp3 carbon atoms, which has been considered to be difficult for conventional Stille coupling reactions. For example, methylation proceeds in a yield of 90% or more when methyl iodide, an excess of tributylphenylstannane, tri-o-tolylphosphine, and unsaturated palladium are allowed to react in a DMF solvent at 60° C. for 5 minutes in the presence of a copper salt and potassium carbonate. This method has been actually applied to prostaglandin derivative tracers, and its usefulness has already been proved, such as successful imaging of prostaglandin receptors in the human brain.
The inventors also have developed a method for rapidly cross-coupling methyl iodide and a large excess of alkenyl stannane or alkynyl stannane (Patent Document 1 and Non-Patent Documents 1 and 2). The inventors also have succeeded in achieving a rapid methylation reaction using an organoboron compound (Patent Document 2).
These Pd(O)-mediated, cross-coupling reactions between sp3 and sp2 hybrid orbital carbon atoms or between sp3 and sp hybrid orbital carbon atoms well proceed in DMF at 60° C. within 5 minutes to give the corresponding methylated products in high yield (Non-Patent Documents 3 and 4). In fact, 15R-[11C]TIC methyl ester, which is a high-functional prostaglandin probe, has been synthesized (85% in HPLC analytical yield) using the sp3-sp2 (aryl) cross-coupling of these techniques, and imaging of a new prostacyclin receptor (IP2) expressed in the central nervous system has been achieved by intravenous injection of the ester into living monkey and human (Non-Patent Documents 5 to 7).
Besides the above, there are some reports on Stille coupling reaction, as set forth below, in connection with the invention (Non-Patent Documents 8 to 15).    Non-Patent Document 1: M. Suzuki, H. Doi, M. Bjorkman, Y. Anderson, B. Langstrom, Y. Watanabe and R. Noyori, Chem. Eur. J., 1997, 3 (12), 2039-2042    Non-Patent Document 2: T. Hosoya, K. Sumi, H. Doi and M. Suzuki, Org. Biomol. Chem., 2006, 4, 410. 415    Non-Patent Document 3: 11C-labeled PGF2 analogue of [p-11C-methyl]MADAM: J. Tarkiainen, J. Vercouillie, P. Emond, J. Sandell, J. Hiltunen, Y. Frangin, D. Guilloteau and C. Halldin, J. Labelled Compd. Radiopharm., 2001, 44, 1013. 1023    Non-Patent Document 4: [11C]celecoxib for imaging COX-2 expression: J. Prabhakaran, V. J. Maio, N. R. Simpson, R. L. V. Heertum, J. J. Mann, J. S. D. Kumar, J. Labelled Compds. Radiopharm. 2005, 48, 887.895.    Non-Patent Document 5: M. Suzuki, R. Noyori, B. Langstrom and Y. Watanabe, Bull. Chem. Soc. Jpn., 2000, 73, 1053. 1070    Non-Patent Document 6: M. Suzuki, H. Doi, T. Hosoya, B. Langstrom and Y. Watanabe, Trends Anal. Chem., 2004, 23, 595. 607    Non-Patent Document 7: R. Noyori, Angew. Chem., Int. Ed. Engl., 2002, 41, 2008. 2022.    Non-Patent Document 8: T. Hosoya, M. Wakao, Y. Kondo, H. Doi, M. Suzuki, “Rapid methylation of terminal acetylenes by the Stille coupling of methyl iodide with alkynyltributylstannanes: a general protocol potentially useful for the synthesis of short-lived 11CH3-labeled PET tracers with 1-propynyl group”, Org. Biomol. Chem., 2, 24-27 (2004).    Non-Patent Document 9: J. Sandell, M. Yu, P. Emond, L. Garreau, S. Chalon, K. Nagren, D. Guilloteau and C. Halldin, Bioorg. Med. Chem. Lett., 12, 3611-3613 (2002).    Non-Patent Document 10: Iida, M. Ogawa, M. Ueda, A. Tominaga, H. Kawashima, Y. Magata, S. Nishiyama, H. Tsukada, T. Mukai and H. Saji, J. Nucl. Med., 45, 878-884 (2004).    Non-Patent Document 11: Y. Huang, R. Narendran, F. Bischoff, N. Guo, Z. Zhu, S.-A Bae, A. S. Lesage and M. Laruelle, J. Med. Chem., 48, 5096-5099 (2005).    Non-Patent Document 12: I. Bennacef, C. Perrio, M. C. Lasne, L. Barre, J. Org. Chem. 72, 2161-2165, (2007).    Non-Patent Document 13: K. Menzel and G. C. Fu, J. Am. Chem. Soc., 2003, 125, 3718-3719    Non-Patent Document 14: H. Tang, K. Menzel and G. C. Fu, Angew, Int. Ed. Engl., 2003, 42, 5079-5082    Non-Patent Document 15: J. Baldwin et al, Angew. Chem. Int. Ed., 2004, 43, 1132-1136    Patent Document 1: WO/02007/046258    Patent Document 2: WO/2008/023780